Current progress in the medical device field is often focused on the combination product, i.e., devices that have a physical or mechanical function as well as pharmaceutical efficacy. One way to accomplish this is via the use of nonbiodegradable or biodegradable polymer systems as drug reservoirs for the combination products. Such polymer systems become the major contact point with tissue and, as such, should be biocompatible. Additionally, as combination products have become more complex, further desirable characteristics have been identified. For example, some polymer systems have been designed to be “biobeneficial,” i.e., the polymers purportedly control protein adsorption and cell deposition (U.S. Pat. No. 7,186,789).
Polymers and polymer systems such as these act as the delivery vehicle for pharmaceutical agents to surrounding tissues and may serve other purposes in a combination product, including physical or mechanical functions. Polymeric delivery vehicles in combination products have taken the form of coatings for stents to deliver drugs (U.S. Pat. Nos. 7,056,591; 7,005,137; 6,953,560 and 6,776,796; and U.S. Pat. Appln. Pub. Nos. 2006/0115449 and 2005/0131201), coatings on surgical meshes to increase handling characteristics and/or for drug delivery (U.S. Pat. Appln. Pub. No. 2007/0198040), coatings for pacemaker pouches to stabilize the tissue pocket and deliver drugs (U.S. Pat. Appln. Pub. No. 2008/0132922), drug-eluting sutures (Ming et al., 2007), and drug-eluting breast implant covers (U.S. Ser. No. 12/058,060, filed Mar. 28, 2008).
As medical providers and patients require greater product performance, the demands placed upon the polymer as an active entity have increased. For example, some of the original stent coatings were polymeric films wrapped around the stent. These films delivered drug directly to the vessel wall by the force of stent expansion with the film being held in place by the stent itself (U.S. Pat. Nos. 5,634,946 and 5,674,287). Current research in the stent coating field focuses on optimizing polymer biocompatibility (WO 2007/056134, U.S. Pat. Nos. 5,317,077; 5,216,115; and 5,099,060), melt viscosity (U.S. Pat. Appln. Pub. No. 2008/0187567), protein adsorption characteristics (U.S. Pat. Appln. Pub. No. 2006/0115449), hydrophilicity, or physicomechanical characteristics (U.S. Pat. Appln. Pub. No. 2005/0131201).
While many polymer classes are known and a variety of those are being used in combination products, synthetic polymers containing the amino acid tyrosine confer many advantages and opportunities to optimize polymer properties. These advantages are partially derived from tyrosine's inherent biocompatibility, lack of toxicity, aromatic nature, and three potential polymerization sites, i.e. the phenolic hydroxyl group, the amino group, and the carboxylic acid group.
One of tyrosine's original uses in a synthetic polymer arose from Kohn's and Langer's work with tyrosine dipeptides wherein an amino-protected tyrosine was dimerized with a tyrosine ester to form a monomeric, diphenolic compound. That di-tyrosine diphenol was copolymerized with dicyanate to produce tyrosine-based polyiminocarbonates to create new immunomodulatory agents (U.S. Pat. No. 4,863,735). Subsequently, Kohn invented several polymeric classes of tyrosine-based polymers in which a tyrosine ester was dimerized with a des-aminotyrosine (i.e., tyrosine lacking its amino group) to form a “tyrosine-derived diphenol.” Those diphenols were condensed with reagents containing two active sites to form several different polymeric classes, including “polyarylates” (polyesters) and polycarbonates (e.g., U.S. Pat. Nos. 7,271,234; RE 37,795E; RE 37,160E; 5,216,115; 5,099,060), polyiminocarbonates (e.g., U.S. Pat. No. 4,980,449), polyethers, polythiocarbonates, polyphosphonates (e.g., U.S. Pat. No. 5,912,225) and others. A later developed group of tyrosine-derived diphenolic polymers, in which the tyrosine side chain ester is converted to a free acid after polymerization has been shown to be an extremely versatile, biocompatible family of materials (U.S. Pat. No. 6,120,491).
Tyrosine-derived diphenolic polyarylates are finding application in antimicrobial-eluting combination devices such as hernia repair meshes and pacemaker covers. They have also been used for combination drug-device products such as drug-eluting stent coatings, breast implant covers, and other applications. Tyrosine-derived diphenolic polycarbonates are being used as fully resorbable cardiovascular stents (Kohn et al., 2005).
Other tyrosine-derived diphenolic polymers have been described by Pacetti et al. (U.S. 2006/0115449). These polymers include tyrosine-derived diphenolic polycarbonates and polyiminocarbonates for use as drug-eluting stent coatings. Pacetti noted that his “tyrosine dipeptide-based bioabsorbable polymers” have mechanical strength advantages because the diphenolic moiety increases rigidity and provides higher glass transition temperatures (Tg). Kohn et al. and Baluca (U.S. Pat. Appln. Pub. Nos. 2008/0187567 and 2008/0112999, respectively) disclosed N-substituted monomers and polymers containing tyrosine-derived diphenols and indicated that protecting the nitrogen appeared to confer a lower glass transition temperature compared to the unprotected species, apparently lowering it enough to confer processability to the materials. Moses et al. have disclosed tyrosine-derived diphenolic monomers and polymers with side chain amides instead of esters (WO 2007/056134).
When copolymerized with the appropriate components, tyrosine provides assets for resorbable combination medical device products such as lack of toxicity, biocompatibility and rigidity. For example, Kohn's tyrosine-derived diphenolic polycarbonates (U.S. Pat. No. 5,198,507) and polyarylates (U.S. Pat. No. 5,216,115) lend rigidity to a device because of their relatively high glass transition temperatures compared to poly-lactic and glycolic acid-based systems. While the glass transition temperature in these polymer families can be moderated by increasing the number of carbons in the backbone or side chain of the polymer (Brocchini et al., 1997), the resorption times for most of these polyarylates are in excess of one year and in excess of 5-10 years for the corresponding polycarbonates (Tangpasuthadol et al., 2000a; Tangpasuthadol et al., 2000b).
Because these polymers do not generally meet the resorption time requirements for the bulk of the resorbable medical products, which require resorption times that vary anywhere from several weeks to several months (e.g., resorbable PGA or PLGA sutures (Ethicon)) to three to six months (cardiovascular stent coatings and/or drug delivery systems (Conor, Biosensors), these polymers are not adequate for many medical needs. Moreover, long resorption times make regulatory hurdles prohibitively expensive because biocompatibility at the implant site of choice may need to be shown through full resorption. For example, any product with a polymer coating that takes 2 years to resorb will require at least a 2-year preclinical program followed by a 2-3 year clinical program in advancing towards regulatory approval.
Thus, the polymer resorption time, along with physicomechanical properties, biocompatibility and drug elution times will contribute to the success of a significant number of combination products. While Kohn reduced the resorption time of the tyrosine-derived diphenolic polyarylates and polycarbonates to a limited extent via the selective introduction of free acid side chains into the diphenolic monomer structures (U.S. Pat. No. 6,120,491), the introduction of those side chains significantly increased the complexity and cost of the synthesis of these materials as well as the glass transition temperature (in some cases, out of the range of polymer processability (U.S. Pat. Appln. Pub. No. 2008/0187567). Furthermore, while the addition of free acid side chains decreased the resorption time for those polymeric fragments containing the free acid side chain, the degradation process still left long polymeric fragments containing ester side chains with resorption times equivalent to those of the original polymer that did not contain the free acid (U.S. Pat. No. 6,120,491).
Therefore, the need remains for a biodegradable, biocompatible family of polymers with resorption times of less than one year, and preferably for a subset with resorption times of less than 6 months that have an accompanying drug elution potential as well as glass transition temperatures in the useful range of 20-85° C. The present invention addresses these shortcomings in the art and more by providing linear polyesteramides formed from aminophenol esters, e.g., tyrosine esters and the like, and diacids in the manner described herein. Moreover, while the polymers of the instant invention can incorporate both free acid side chains and esterified side chains, these polymers do not require the presence of free acid side chains to provide fast resorption times, making them cheaper and easier to synthesize than the polymers disclosed in U.S. Pat. No. 6,120,491.